Robotic Mouse

  • Emmanuelle Bitoun
  • Peter L. Oliver
  • Kay E. Davies
Reference work entry

Abstract

Gene targeting is a very powerful approach for the generation of clinically relevant mouse models to elucidate the underlying molecular basis of cerebellar disorders. However, with the etiology of the vast majority of these conditions still unknown, a complementary approach based on large-scale random mutagenesis is now being employed to identify new genes and downstream signaling pathways that control neuronal cell death and survival in the cerebellum. This chapter presents the characterization of the robotic mouse, a novel model of autosomal dominant cerebellar ataxia isolated from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, which shows general growth retardation, adult-onset region-specific Purkinje cell (PC) loss, cataracts, and defects in early T-cell maturation. The mutated protein ALL1-fused gene from chromosome 4 (AF4), which functions as a cofactor of RNA polymerase II (Pol II) elongation and disruptor of telomeric silencing-1 (DOT1)-mediated chromatin remodeling during transcription, abnormally accumulates in PCs of the cerebellum due to a slower turnover by the ubiquitin-proteasome pathway. This results in the sustained transcriptional repression of the PC survival factor insulin-like growth factor 1 (IGF-1) and deficits in downstream signaling activation, leading to degeneration and eventually death of PCs. The identification of AF4 and DOT1 as the first transcriptional negative regulators of IGF-1 expression in the cerebellum opens new avenues of research into the manipulation of this pathway for the treatment of cerebellar ataxia. In addition, the functional conservation among the AF4-related proteins implies that deregulation of transcriptional elongation and chromatin remodeling may also underlie the pathogenesis of other disorders of the central nervous system (CNS), in particular mental retardation. The robotic mouse has revealed a critical novel function for AF4 in the cerebellum which could not have been predicted otherwise, and has been instrumental in the elucidation of the relevant transcriptional regulatory mechanisms.

Keywords

Purkinje Cell Cerebellar Ataxia Mixed Lineage Leukemia Autosomal Dominant Cerebellar Ataxia Purkinje Cell Loss 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Andersen BB, Korbo L, Pakkenberg B (1992) A quantitative study of the human cerebellum with unbiased stereological techniques. J Comp Neurol 326:549–560PubMedCrossRefGoogle Scholar
  2. Bains M, Florez-McClure ML, Heidenreich KA (2009) IGF-I prevents the accumulation of autophagic vesicles and cell death in Purkinje neurons by increasing the rate of autophagosome-to-lysosome fusion and degradation. J Biol Chem 284:20398–20407PubMedCrossRefGoogle Scholar
  3. Baker J, Liu JP, Robertson EJ et al (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73–82PubMedGoogle Scholar
  4. Barry ER, Corry GN, Rasmussen TP (2010) Targeting DOT1L action and interactions in leukemia: the role of DOT1L in transformation and development. Expert Opin Ther Targets 14:405–418PubMedCrossRefGoogle Scholar
  5. Baskaran K, Erfurth F, Taborn G et al (1997) Cloning and developmental expression of the murine homolog of the acute leukemia proto-oncogene AF4. Oncogene 15:1967–1978PubMedCrossRefGoogle Scholar
  6. Becker EB, Oliver PL, Glitsch MD et al (2009) A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice. Proc Natl Acad Sci USA 106:6706–6711PubMedCrossRefGoogle Scholar
  7. Bitoun E, Davies KE (2005) The robotic mouse: unravelling the function of AF4 in the cerebellum. Cerebellum 4:1–11CrossRefGoogle Scholar
  8. Bitoun E, Davies KE (2009) The robotic mouse: understanding the role of AF4, a cofactor of transcriptional elongation and chromatin remodelling, in Purkinje cell function. Cerebellum 8:175–183PubMedCrossRefGoogle Scholar
  9. Bitoun E, Oliver PL, Davies KE (2007) The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum Mol Genet 16:92–106PubMedCrossRefGoogle Scholar
  10. Bitoun E, Finelli MJ, Oliver PL et al (2009) AF4 is a critical regulator of the IGF-1 signaling pathway during Purkinje cell development. J Neurosci 29:15366–15374PubMedCrossRefGoogle Scholar
  11. Brown SD, Nolan PM (1998) Mouse mutagenesis-systematic studies of mammalian gene function. Hum Mol Genet 7:1627–1633PubMedCrossRefGoogle Scholar
  12. Caston J, Vasseur F, Delhaye-Bouchaud N et al (1997) Delayed spontaneous alternation in intact and cerebellectomized control and lurcher mutant mice: differential role of cerebellar cortex and deep cerebellar nuclei. Behav Neurosci 111:214–218PubMedCrossRefGoogle Scholar
  13. Chahrour M, Jung SY, Shaw C et al (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320:1224–1229PubMedCrossRefGoogle Scholar
  14. Chaible LM, Corat MA, Abdelhay E et al (2010) Genetically modified animals for use in research and biotechnology. Genet Mol Res 9:1469–1482PubMedCrossRefGoogle Scholar
  15. Ebong S, Chepelinsky AB, Robinson ML et al (2004) Characterization of the roles of STAT1 and STAT3 signal transduction pathways in mammalian lens development. Mol Vis 10:122–131PubMedGoogle Scholar
  16. Elrick MJ, Pacheco CD, Yu T et al (2010) Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. Hum Mol Genet 19:837–847PubMedCrossRefGoogle Scholar
  17. Erfurth F, Hemenway CS, de Erkenez AC et al (2004) MLL fusion partners AF4 and AF9 interact at subnuclear foci. Leukemia 18:92–102PubMedCrossRefGoogle Scholar
  18. Estable MC, Naghavi MH, Kato H et al (2002) MCEF, the newest member of the AF4 family of transcription factors involved in leukemia, is a positive transcription elongation factor-b-associated protein. J Biomed Sci 9:234–245PubMedCrossRefGoogle Scholar
  19. Faivre L, Radford I, Viot G et al (2000) Cerebellar ataxia and mental retardation in a child with an inherited satellited chromosome 4q. Ann Génét 43:35–38PubMedCrossRefGoogle Scholar
  20. Fernandez AM, Carro EM, Lopez-Lopez C et al (2005) Insulin-like growth factor I treatment for cerebellar ataxia: addressing a common pathway in the pathological cascade? Brain Res Brain Res Rev 50:134–141PubMedCrossRefGoogle Scholar
  21. Ford GD, Ford BD, Steele EC et al (2008) Analysis of transcriptional profiles and functional clustering of global cerebellar gene expression in PCD3J mice. Biochem Biophys Res Commun 377:556–561PubMedCrossRefGoogle Scholar
  22. Fukudome Y, Tabata T, Miyoshi T et al (2003) Insulin-like growth factor-I as a promoting factor for cerebellar Purkinje cell development. Eur J Neurosci 17:2006–2016PubMedCrossRefGoogle Scholar
  23. Gatchel JR, Watase K, Thaller C et al (2008) The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. Proc Natl Acad Sci USA 105:1291–1296PubMedCrossRefGoogle Scholar
  24. Gecz J, Gedeon AK, Sutherland GR et al (1996) Identification of the gene FMR2, associated with FRAXE mental retardation. Nat Genet 13:105–108PubMedCrossRefGoogle Scholar
  25. Gerber M, Shilatifard A (2003) Transcriptional elongation by RNA polymerase II and histone methylation. J Biol Chem 278:26303–26306PubMedCrossRefGoogle Scholar
  26. Goold R, Hubank M, Hunt A et al (2007) Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1. Hum Mol Genet 16:2122–2134PubMedCrossRefGoogle Scholar
  27. Gu Y, Nakamura T, Alder H et al (1992) The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71:701–708PubMedCrossRefGoogle Scholar
  28. Hillman MA, Gecz J (2001) Fragile XE-associated familial mental retardation protein 2 (FMR2) acts as a potent transcription activator. J Hum Genet 46:251–259PubMedCrossRefGoogle Scholar
  29. Iida S, Seto M, Yamamoto K et al (1993) MLLT3 gene on 9p22 involved in t(9;11) leukemia encodes a serine/proline rich protein homologous to MLLT1 on 19p13. Oncogene 8:3085–3092PubMedGoogle Scholar
  30. Isaacs AM, Oliver PL, Jones EL et al (2003) A mutation in Af4 is predicted to cause cerebellar ataxia and cataracts in the robotic mouse. J Neurosci 23:1631–1637PubMedGoogle Scholar
  31. Isnard P, Depetris D, Mattei MG et al (1998) cDNA cloning, expression and chromosomal localization of the murine AF-4 gene involved in human leukemia. Mamm Genome 9:1065–1068PubMedCrossRefGoogle Scholar
  32. Isnard P, Core N, Naquet P et al (2000) Altered lymphoid development in mice deficient for the mAF4 proto-oncogene. Blood 96:705–710PubMedGoogle Scholar
  33. Kapfhammer JP (2004) Cellular and molecular control of dendritic growth and development of cerebellar Purkinje cells. Prog Histochem Cytochem 39:131–182PubMedCrossRefGoogle Scholar
  34. Lalonde R (2002) The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 26:91–104PubMedCrossRefGoogle Scholar
  35. Lalonde R, Manseau M, Botez MI (1987) Delayed spontaneous alternation in Purkinje cell degeneration mutant mice. Neurosci Lett 80:343–346PubMedCrossRefGoogle Scholar
  36. Landreth KS, Narayanan R, Dorshkind K (1992) Insulin-like growth factor-I regulates pro-B cell differentiation. Blood 80:1207–1212PubMedGoogle Scholar
  37. Lang-Rollin I, Rideout H, Stefanis L (2003) Ubiquitinated inclusions and neuronal cell death. Histol Histopathol 18:509–517PubMedGoogle Scholar
  38. Marshall NF, Peng J, Xie Z et al (1996) Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J Biol Chem 271:27176–27183PubMedCrossRefGoogle Scholar
  39. Menken M, Munsat TL, Toole JF (2000) The global burden of disease study: implications for neurology. Arch Neurol 57:418–420PubMedCrossRefGoogle Scholar
  40. Mueller D, Bach C, Zeisig D et al (2007) A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110:4445–4454PubMedCrossRefGoogle Scholar
  41. Nilson I, Reichel M, Ennas MG et al (1997) Exon/intron structure of the human AF-4 gene, a member of the AF-4/LAF-4/FMR-2 gene family coding for a nuclear protein with structural alterations in acute leukaemia. Br J Haematol 98:157–169PubMedCrossRefGoogle Scholar
  42. Nolan PM, Peters J, Strivens M et al (2000) A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nat Genet 25:440–443PubMedCrossRefGoogle Scholar
  43. Okada Y, Feng Q, Lin Y et al (2005) hDOT1L links histone methylation to leukemogenesis. Cell 121:167–178PubMedCrossRefGoogle Scholar
  44. Oldfors A, Sourander P, Armstrong DL et al (1990) Rett syndrome: cerebellar pathology. Pediatr Neurol 6:310–314PubMedCrossRefGoogle Scholar
  45. Oliver PL, Davies KE (2005) Analysis of human neurological disorders using mutagenesis in the mouse. Clin Sci 108:385–397PubMedCrossRefGoogle Scholar
  46. Oliver PL, Bitoun E, Clark J et al (2004) Mediation of Af4 protein function in the cerebellum by SIAH proteins. Proc Natl Acad Sci USA 101:14901–14906PubMedCrossRefGoogle Scholar
  47. Oliver PL, Bitoun E, Davies KE (2007a) Comparative genetic analysis: the utility of mouse genetic systems for studying human monogenic disease. Mamm Genome 18:412–424PubMedCrossRefGoogle Scholar
  48. Oliver PL, Keays DA, Davies KE (2007b) Behavioural characterisation of the robotic mouse mutant. Behav Brain Res 181:239–247PubMedCrossRefGoogle Scholar
  49. Prasad R, Yano T, Sorio C et al (1995) Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia. Proc Natl Acad Sci USA 92:12160–12164PubMedCrossRefGoogle Scholar
  50. Rudelius M, Osanger A, Kohlmann S et al (2006) A missense mutation in the WD40 domain of murine Lyst is linked to severe progressive Purkinje cell degeneration. Acta Neuropathol 112:267–276PubMedCrossRefGoogle Scholar
  51. Sachs AJ, Schwendinger JK, Yang AW (2007) The mouse mutants recoil wobbler and nmf373 represent a series of Grm1 mutations. Mamm Genome 18:749–756PubMedCrossRefGoogle Scholar
  52. Sarna J, Miranda SR, Schuchman EH et al (2001) Patterned cerebellar Purkinje cell death in a transgenic mouse model of Niemann Pick type A/B disease. Eur J Neurosci 13:1873–1880PubMedCrossRefGoogle Scholar
  53. Shibuya N, Taki T, Mugishima H et al (2001) t(10;11)-acute leukemias with MLL-AF10 and MLL-ABI1 chimeric transcripts: specific expression patterns of ABI1 gene in leukemia and solid tumor cell lines. Genes Chromosom Cancer 32:1–10PubMedCrossRefGoogle Scholar
  54. Srinivasan RS, Nesbit JB, Marrero L et al (2004) The synthetic peptide PFWT disrupts AF4-AF9 protein complexes and induces apoptosis in t(4;11) leukemia cells. Leukemia 18:1364–1372PubMedCrossRefGoogle Scholar
  55. Steichen-Gersdorf E, Gassner I, Superti-Furga A et al (2008) Triangular tibia with fibular aplasia associated with a microdeletion on 2q11.2 encompassing LAF4. Clin Genet 74:560–565PubMedCrossRefGoogle Scholar
  56. Taki T, Kano H, Taniwaki M et al (1999) AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Proc Natl Acad Sci USA 96:14535–14540PubMedCrossRefGoogle Scholar
  57. Torres-Aleman I, Pons S, Santos-Benito FF (1992) Survival of Purkinje cells in cerebellar cultures is increased by insulin-like growth factor I. Eur J Neurosci 4:864–869PubMedCrossRefGoogle Scholar
  58. Tropea D, Giacometti E, Wilson NR et al (2009) Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA 106:2029–2034PubMedCrossRefGoogle Scholar
  59. Urdinguio RG, Lopez-Serra L, Lopez-Nieva P et al (2008) Mecp2-null mice provide new neuronal targets for Rett syndrome. PLoS ONE 3:e3669PubMedCrossRefGoogle Scholar
  60. Villalba M, Bockaert J, Journot L (1997) Concomitant induction of apoptosis and necrosis in cerebellar granule cells following serum and potassium withdrawal. Neuroreport 8:981–985PubMedCrossRefGoogle Scholar
  61. von Bergh AR, Beverloo HB, Rombout P et al (2002) LAF4, an AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia. Genes Chromosom Cancer 35:92–96CrossRefGoogle Scholar
  62. Welniak LA, Sun R, Murphy WJ (2002) The role of growth hormone in T-cell development and reconstitution. J Leukoc Biol 71:381–387PubMedGoogle Scholar
  63. Xu X, Kedlaya R, Higuchi H et al (2010) Mutation in archain 1, a subunit of COPI coatomer complex, causes diluted coat color and Purkinje cell degeneration. PLoS Genet 6:e1000956PubMedCrossRefGoogle Scholar
  64. Yamada M, Sato T, Tsuji S et al (2008) CAG repeat disorder models and human neuropathology: similarities and differences. Acta Neuropathol 115:71–86PubMedCrossRefGoogle Scholar
  65. Yik JH, Chen R, Nishimura R et al (2003) Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Mol Cell 12:971–982PubMedCrossRefGoogle Scholar
  66. Zeisig DT, Bittner CB, Zeisig BB et al (2005) The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Oncogene 24:5525–5532PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Emmanuelle Bitoun
    • 1
  • Peter L. Oliver
    • 1
  • Kay E. Davies
    • 1
  1. 1.Department of Physiology, Anatomy and Genetics, MRC Functional Genomics UnitUniversity of OxfordOxfordUK

Personalised recommendations